All-optical interrogation of the hippocampal neural code underlying episodic memory

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Our ability to form memories of specific events, known as episodic memory, is central to our identity and our interactions with the world. A key brain structure involved in storing and retrieving episodic memories is the hippocampus. Lesions of the hippocampus, or disruptions of the hippocampal circuit during neurodegenerative diseases such as Alzheimer's, can disrupt recall of existing memories and prevent formation of new episodic memories. The discovery of place cells in the hippocampus, which are active in specific regions of the environment, provided a possible cellular mechanism supporting the formation of episodic memories. However, it is not yet known whether place cell firing is causally linked to memory formation. Furthermore, the nature of the neural code that the hippocampus utilises to store and retrieve memories across space and time is unknown. We will address these fundamental questions by harnessing a novel strategy for 'all-optical' interrogation of neural circuits in the intact brain. This approach uses light to simultaneously read out the activity of neurons while performing targeted optogenetic stimulation with cellular resolution in behaving mice. This allows us to identify neurons which exhibit certain types of activity and to stimulate them selectively in order to test the causal functional role of this activity, which we can assess by observing the behavioural performance of the animal. By changing the number, timing and pattern of activated neurons in the circuit we can identify the neural code which supports episodic memory.Our experiments will probe the role of hippocampal neurons in the formation of both spatial and temporal aspects of episodic memory. We will use two different behavioural tasks in order to identify and manipulate the relevant neural codes. For spatial memory, mice will perform a spatial navigation task in a virtual reality environment, running down a track and learning to stop and lick in an area where they receive a reward. For temporal memory we will use an olfactory task where animals must remember the identity of an odor across a delay and then assess its relationship to a second odor. We will then use all-optical interrogation to test both memory formation and retrieval by identifying and artificially increasing the reliability of the relevant activity patterns in order to increase learning rates on both tasks. Additionally, we will test the role of place cells and sequences in memory retrieval by artificially driving these patterns and observing relevant behavioural alterations. Building upon this initial test of function we will then systematically vary our stimulation parameters, including the number of cells, level of synchrony and pattern of sequential activation. This will provide the first causal links between specific activity patterns of hippocampal neurons and behaviour, as well as revealing the fundamental properties of the neural code underlying episodic memory.By determining the neural activity patterns enabling memory we will substantially further our understanding of both the healthy and diseased brain. Our knowledge of how disease states impact the manifestation of healthy neural activity patterns is still limited, in part because we do not yet know the nature of the neural code in the healthy brain. Once the activity patterns supporting memory in the healthy brain are understood, new treatments can be designed to preserve or restore them when the diseased brain malfunctions. Our findings will be especially important for guiding research in dementias and neurodegenerative diseases, which cause cognitive deficits due to disruptions of cellular function and coding in the hippocampal system.